Joint study on design, synthesis and analysis of agonists and antagonists of galanin

甘丙肽是一种含有29个氨基酸残基的神经肽，在大脑和外周都具有多种生物活性。1)本实验室采用固相技术和常规溶液法合成了23个甘丙素相关多肽。2)比较了人、大鼠和猪甘丙素对13.9 mM葡萄糖刺激的胰岛素释放和葡萄糖诱导的大鼠胰腺胰岛素释放的影响。其中大鼠甘丙素对葡萄糖诱导的胰岛素释放的抑制作用最强。M分别抑制GRP(14-27)刺激的胃泌素释放。4)人和大鼠甘丙素以及猪甘丙素抑制环肌…的收缩反应。更多的e分别以剂量依赖的方式出现。甘丙素(1-15)-醇等甘丙素具有几乎相同的抑制作用。这些结果有力地表明，甘丙素在分子的氨基末端半部分存在抑制神经诱发的环状肌肉收缩的活性部位。5)甘丙素抑制隐神经制剂0.01muM引起的c-纤维反应，较高浓度(1-3muM)的甘丙肽部分抑制了单突触反射。人甘丙肽最强，猪甘丙素最弱。6)[D-Trp^-lt；8，9&gt；]-Galanin(1-15)-ol和[D-Thr^6，D-Trp^&lt；8，9&gt；]-Galanin(1-15)-ol在体外对葡萄糖刺激的胰岛素释放有拮抗作用，而由甘丙素(1-13)和P物质(5-11)组成的多肽Galantide在10^&lt；-7&gt；M处没有拮抗作用。尤其是[D-Thr^6，D-Trp^&lt；8，9&gt；]-Galanin(1-15)-ol在10^&lt；-7&gt；M可完全阻断10^&lt；-9&gt；M大鼠胰腺的抑制作用。这些结合位点也存在于缺乏或具有极少甘丙素(1-29)结合位点的几个区域，如背侧海马结构、新皮质和新纹状体。8)神经肽与P物质和其他速激肽的共存和相互作用，特别是甘丙素。由于甘丙蛋白和相关多肽在细胞或细胞外调节机制中的重要性及其潜在的治疗价值，了解它们与特定受体的详细相互作用将为结构活性研究提供有用的信息。在这项国际联合研究中，对这一问题采取了多种方法，11月份在静冈举行的研讨会帮助取得了丰硕成果和成功。较少

The neuropeptide galanin with 29 amino acid residues has been known to have numerous biological activities, both in the brain and in the periphery. The following studies have been carried out under International Joint study on Design, Synthesis and Analysis of Agonists Antagonists of Galanin.1) Twenty-three galanin-related peptides were synthesized by solid phase technology or conventional solution method in our laboratory (N.Yanaihara).2) Effects of human, rat and porcine galanins on 13.9mM glucose-stimulated insulin release were compared on glucose-induced insulin release in isolated rat pancreas.Among them, rat galanin showed the highest inhibition of glucose induced insulin release.3) Human and rat galanins as well as porcine galanin at 10^<-8>M inhibited GRP(14-27) stimulated gastrin release, respectively. Among them, rat galanin was the weakest in this system.4) Human and rat galanins as well as porcine galanin at 10^<-6>M suppressed the contractile response of the circular muscl … More e in a dose dependent manner, respectively. The galanins including galanin (1-15)-ol showed nearly equipotent inhibitory effect. These results suggest strongly the existence of the active site of galanin for its suppression of neurally-evoked circular muscle contractions in the amino-terminal half of the molecule.5) Galanins depressed the c-fiber response evoked by saphenous never preparation 0.01muM and higher concentrations (1-3muM) partially inhibited the monosynaptic reflex. Human galanin was the most potent and porcine galanin was the weakest. The amino-terminal fragment, galanin(1-15)-ol showed very weak effects.6) Both [D-Trp^<8,9>]-galanin (1-15)-ol and [D-Thr^6,D-trp^<8,9>]-galanin (1-15)-ol were found to act as antagonist on glucose-stimulated insulin release in vitro, while galantide, a peptide comprising galanin (1-13) and substance P(5-11), at 10^<-7>M did not show any antagonistic activity in this system. Especially, [D-Thr^6,D-Trp^<8,9>]-galanin (1-15)-ol at 10^<-7>M completely abolished the inhibitory effect of 10^<-9>M rat galanin in the isolated perfused rat pancreas.7) The existence and widespread distribution of specific [^<125>I] galanin (1-15) fragment binding sites in the rat brain was demonstrated. These binding sites were also present in several areas lacking or having very few [^<125>I] galanin (1-29) binding sites, such as the dorsal hippocampal formation, the neocortex and the neostriatum.8) Coexistence and interaction of neuropeptides with substance P and other tachykinins, with special reference to galanin were demonstrated.Because of the importance of galanin and the related peptides in the role of cellular or extracellular regulatory mechanisms and their potential therapeutic value, and understanding of their detailed interactions with the specific receptor would provide useful information for structure-activity study. A variety of approach to this problems have been performed in this international joint study, And Symposium help in November in Shizuoka was really fruitful and successful. Less